Clinical impact and practical use of sodium-glucose cotransporter 2 inhibitors for patients with chronic kidney disease
Article information
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have transformed the treatment of both cardiovascular and renal diseases. Although originally developed for glycemic control in type 2 diabetes mellitus, these agents have demonstrated significant benefits by reducing cardiovascular events and slowing the progression of kidney disease, even in patients without diabetes. Landmark trials, including EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and DAPA-HF, consistently demonstrated reductions in heart failure hospitalizations and renal deterioration among patients at high cardiovascular risk. However, many of these studies excluded patients with advanced chronic kidney disease (CKD), limiting the generalizability of their findings for this population. More recent investigations, such as CREDENCE, DAPA-CKD, and EMPA-KIDNEY, have focused on patients with CKD and confirmed that SGLT2 inhibitors offer significant renal and cardiovascular protection regardless of diabetic status. This review summarizes key clinical trials, outlining their design and outcomes with a particular emphasis on inclusion and exclusion criteria and the implications for CKD populations. Further, it discusses the practical application and safety considerations of SGLT2 inhibitors in nephrology, underscoring their emerging role as a fundamental therapeutic strategy in CKD management.
INTRODUCTION
Chronic kidney disease (CKD) poses a significant global health challenge by contributing to elevated morbidity, mortality, and healthcare costs. Cardiovascular (CV) disease remains the leading cause of death among CKD patients, while conventional therapies have shown limited efficacy in slowing renal function decline or reducing CV events in this group. Over the past decade, sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a novel therapeutic class that was initially introduced for glycemic control in patients with type 2 diabetes mellitus (T2DM). Beyond their glucose-lowering effects, these agents have demonstrated remarkable benefits in reducing hospitalizations for heart failure (HF) and decelerating renal disease progression. Large randomized controlled trials (RCTs) have firmly established the role of SGLT2 inhibitors in patients at high CV risk. Nevertheless, the generalizability of these findings to individuals with moderate to advanced CKD remains uncertain because many landmark studies excluded patients with severely impaired kidney function. More recent dedicated trials involving CKD populations have addressed this gap, establishing SGLT2 inhibitors as a cornerstone in kidney disease management. This review examines the clinical evidence supporting SGLT2 inhibitors in both general and CKD-specific populations, offering practical insights for their application in nephrology.
PHARMACOKINETICS, PHARMACODYNAMICS, AND MECHANISM OF ACTION
SGLT2 inhibitors are orally administered agents that are primarily absorbed in the gastrointestinal tract. They undergo minimal hepatic metabolism and are largely excreted unchanged via the kidneys. Their pharmacodynamic effects are dose-dependent and correlate with renal glucose filtration [1–3]. The primary mechanism involves the inhibition of SGLT2 in the proximal convoluted tubules of the nephron. By blocking this transporter, the drugs reduce the reabsorption of filtered glucose, thereby promoting glucosuria and mild natriuresis [1–3]. Although the glucose-lowering effect diminishes as kidney function declines, SGLT2 inhibitors maintain renal and CV protective mechanisms independent of glycemic control. These benefits include improved tubuloglomerular feedback, reduced intraglomerular pressure, modulation of inflammatory and fibrotic pathways, and enhanced myocardial metabolism [1–3].
EVIDENCE FROM MAJOR CLINICAL TRIALS
Several large-scale RCTs have demonstrated the efficacy of SGLT2 inhibitors in improving CV and renal outcomes across various patient populations. The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial enrolled 7,020 patients with T2DM and established CV disease, reporting a 14% relative risk reduction in major adverse CV events (MACE) and a 35% decrease in HF hospitalizations [1]. Similarly, the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program—pooling data from two trials and involving over 10,000 participants—demonstrated a significant reduction in CV events along with a slower progression of albuminuria [2]. The DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) trial, which included more than 17,000 patients, confirmed the benefit of dapagliflozin in reducing HF hospitalizations, although its effect on MACE was more modest [3]. In the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, dapagliflozin 10 mg significantly reduced MACE—including worsening HF, CV death, and all-cause mortality—in patients with symptomatic HF and reduced left ventricular ejection fraction compared to placebo [4]. These trials primarily excluded individuals with advanced CKD, thereby prompting the need for dedicated renal studies.
The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial was the first dedicated study of renal outcomes, enrolling 4,401 patients with T2DM and CKD [5]. In this trial, canagliflozin reduced the composite outcome of end-stage renal disease (ESRD), a doubling of serum creatinine, or death from renal or CV causes by 30%. The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial was noteworthy for including patients with and without diabetes [6]; dapagliflozin produced a 39% reduction in the composite outcome of sustained estimated glomerular filtration rate (eGFR) decline (≥50%), ESRD, or CV/renal death. EMPA-KIDNEY (Study of Heart and Kidney Protection with Empagliflozin) further expanded the study population to include patients with nondiabetic CKD, demonstrating a 28% reduction in the primary outcome of kidney disease progression or CV death [7]. Table 1 summarizes the inclusion and exclusion criteria, primary outcomes, and key findings of the major RCTs involving SGLT2 inhibitors [1–7].
Summary of major SGLT2 inhibitor trials
META-ANALYSES AND REAL-WORLD EVIDENCE
Meta-analyses have confirmed these results. A comprehensive analysis by Neuen et al. [8], which evaluated over 90,000 patients across multiple RCTs, concluded that SGLT2 inhibitors consistently reduce kidney disease progression and HF risk irrespective of baseline eGFR or diabetes status. Zelniker et al. [9] emphasized the robust benefits regarding HF outcomes, particularly among patients with reduced ejection fraction. Real-world studies, such as CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) and EMPRISE (Empagliflozin Comparative Effectiveness and Safety), have supported the generalizability of these trial findings [10,11]. The CVD-REAL study, which included over 300,000 patients from several countries, demonstrated reductions in HF hospitalizations and all-cause mortality compared with other glucose-lowering agents [10]. The EMPRISE study, focusing on empagliflozin, showed a reduction in both hospitalizations for HF and the decline in kidney function under routine clinical practice [11].
SAFETY AND TOLERABILITY
SGLT2 inhibitors are generally well tolerated; however, clinicians should remain aware of potential adverse effects. The most frequently reported side effects are genital mycotic infections, particularly in women, resulting from increased glycosuria. Volume depletion may also occur, especially in older patients or those on diuretics, warranting regular monitoring of volume status [12]. Euglycemic diabetic ketoacidosis, though rare, can be serious and requires vigilance regarding precipitating factors such as prolonged fasting, acute illness, or surgical stress [12]. In these scenarios, SGLT2 inhibitors should be temporarily discontinued. Urinary tract infections and increased frequency of urination are generally mild but should nonetheless be monitored. Renal-related adverse events are uncommon, and current evidence indicates that when used appropriately, these agents do not increase the risk of acute kidney injury [12].
GUIDELINE RECOMMENDATIONS AND CLINICAL APPLICATIONS
Multiple international guidelines have endorsed the use of SGLT2 inhibitors in CKD. The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend initiating an SGLT2 inhibitor in patients with T2DM and CKD when eGFR is ≥30 mL/min/1.73 m2 and albuminuria is present, continuing therapy until dialysis initiation [13]. The American Diabetes Association supports the use of SGLT2 inhibitors for both renal and CV protection in patients with T2DM and high-risk features [14]. Additionally, European Society of Cardiology guidelines emphasize the role of these agents in managing HF and reducing CKD risk [15]. In clinical practice, SGLT2 inhibitors should be integrated into a multidisciplinary treatment strategy that includes renin-angiotensin system blockade, lifestyle interventions, and CV risk management.
EVIDENCE OF SGLT2 INHIBITOR ACTIONS ACCORDING TO CKD SEVERITY
SGLT2 inhibitor effectiveness in patients with eGFR <30 mL/min/1.73 m2
Historically, concerns regarding diminished glycemic efficacy led to the exclusion of patients with eGFR <30 mL/min/1.73 m2 from early SGLT2 inhibitor trials [1–3]. However, recent studies have demonstrated that although the glucose-lowering effect may be diminished, the CV and renal protective benefits are maintained. The EMPA-KIDNEY trial, which included a substantial proportion of patients with eGFR <30 mL/min/1.73 m2, reported a 28% reduction in the composite outcome of kidney disease progression or CV death [7]. Meta-analyses have also confirmed that SGLT2 inhibitors reduce hospitalizations for HF and slow the decline in eGFR in this population [16,17]. Consequently, updated recommendations now support their use in patients with eGFR as low as 20 mL/min/1.73 m2 for organ protection.
SGLT2 inhibitor efficacy in patients with eGFR 30–40 mL/min/1.73 m2
Patients with moderate renal impairment—particularly those with an eGFR between 30 and 40 mL/min/1.73 m2—comprise a substantial segment of the CKD population. Subgroup analyses from the DAPA-CKD and EMPA-KIDNEY trials confirm that the renal and CV benefits of SGLT2 inhibitors remain consistent in this patient group [6,7]. In DAPA-CKD, patients with an eGFR of 30 to 45 mL/min/1.73 m2 experienced a 44% relative risk reduction in the primary composite renal endpoint [6]. Similarly, EMPA-KIDNEY demonstrated benefits across all eGFR strata, including the 30 to 45 mL/min/1.73 m2 range, supporting the continued use of SGLT2 inhibitors in this stage of CKD [7].
SGLT2 inhibitor use in ESRD
The use of SGLT2 inhibitors in patients with ESRD on dialysis remains uncertain because most major trials have excluded this population. In current clinical practice, these agents can be initiated in patients with an eGFR of 20 mL/min/1.73 m2 or higher but should be discontinued upon the initiation of dialysis for ESRD [18]. This approach likely reflects the diminished efficacy of SGLT2 inhibitors in promoting glucosuria and natriuresis as kidney function declines, combined with the uncertain safety profile in ESRD patients [18]. According to the DAPA-CKD and EMPA-KIDNEY trials, SGLT2 inhibitors were associated with significant improvements in adverse renal and CV outcomes even within the stage 4 CKD population [6,7]. In addition to their CV benefits, SGLT2 inhibitors provide indirect advantages—such as anti-inflammatory effects, mitigation of endoplasmic reticulum stress, reduction of reactive oxidative stress, and regulation of autophagy—which may improve CV function even in ESRD and hemodialysis patients [18]. Building on these findings, several clinical studies (e.g., ClinicalTrials.gov identifiers: NCT06249945, NCT06182839, NCT05374291) are currently underway [18,19].
FUTURE DIRECTIONS
Several research avenues remain open. Ongoing studies are evaluating the effects of SGLT2 inhibitors in patients with nonalbuminuric CKD, primary glomerular diseases, and autosomal dominant polycystic kidney disease [20]. Trials combining SGLT2 inhibitors with other kidney-protective agents, such as nonsteroidal mineralocorticoid receptor antagonists or GLP-1 receptor agonists, may offer synergistic benefits. Additionally, biomarker studies may help identify patient populations that are most likely to benefit [19,20].
CONCLUSIONS
SGLT2 inhibitors have emerged as a foundational therapy for CKD patients by providing robust protection against kidney function decline, HF hospitalizations, and CV death. Their benefits extend beyond glycemic control, as evidenced even in patients without diabetes. Recent evidence supports their safe and effective use in patients with reduced eGFR—even down to 20 mL/min/1.73 m2. Real-world data and guideline recommendations are now aligned with clinical trial evidence, reinforcing the value of these agents in routine nephrology practice. As new indications and therapeutic strategies emerge, SGLT2 inhibitors are likely to remain central to the management of CKD.
Notes
Conflicts of interest
The author has no conflicts of interest to declare.
Funding
The author received no financial support for this study.